## First-Line Treatment of mCRPC **Key Point:** Abiraterone acetate is the preferred first-line agent for metastatic castration-resistant prostate cancer (mCRPC) in patients who have not yet received chemotherapy, particularly those with visceral or bone metastases. ### Mechanism of Action Abiraterone acetate is a selective inhibitor of CYP17A1 (17α-hydroxylase/17,20-lyase), which blocks both testicular and adrenal androgen synthesis. This dual blockade is more potent than GnRH agonists alone and addresses the castration-resistant phenotype. ### Clinical Evidence - **COU-AA-302 trial** demonstrated that abiraterone + prednisone + ADT significantly improved overall survival (OS) and radiographic progression-free survival (rPFS) in chemotherapy-naïve mCRPC patients. - Median OS benefit: ~15 months improvement over placebo. - Particularly effective in patients with bone metastases (as in this case). ### Dosing & Administration - **Dose:** 1000 mg once daily + prednisone 5 mg twice daily - **Requirement:** Must be given with food (fatty meal enhances absorption) - Requires monitoring for hypokalemia and hypertension due to mineralocorticoid excess ### Comparison with Other Agents | Agent | First-Line Role | Key Indication | Timing | |-------|-----------------|----------------|--------| | **Abiraterone** | Yes (chemotherapy-naïve) | mCRPC, bone mets, visceral disease | Before docetaxel | | **Enzalutamide** | Yes (alternative) | mCRPC, high-risk features | Before docetaxel | | **Docetaxel** | No (second-line) | After hormone therapy failure | Post-abiraterone/enzalutamide | | **Cabazitaxel** | No (third-line) | Post-docetaxel resistance | After docetaxel failure | **High-Yield:** Both abiraterone and enzalutamide are acceptable first-line choices for chemotherapy-naïve mCRPC, but abiraterone is traditionally preferred in bone-predominant disease and was the first agent approved in this setting (COU-AA-302 predated AFFIRM trial for enzalutamide in this population). **Clinical Pearl:** Abiraterone requires prednisone co-administration to suppress ACTH-driven adrenal stimulation and prevent hypokalemia/hypertension from excess mineralocorticoid activity. ### Why Docetaxel Is Not First-Line Here Docetaxel is reserved for patients who have progressed on or are ineligible for hormone-based therapies (abiraterone/enzalutamide). It is chemotherapy and carries greater toxicity; hormone therapy is tried first in chemotherapy-naïve patients.
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